Lomonosova E, Chinnadurai G
Institute for Molecular Virology, Saint Louis University School of Medicine, Doisy Research Center, St Louis, MO 63104, USA.
Oncogene. 2008 Dec;27 Suppl 1(Suppl 1):S2-19. doi: 10.1038/onc.2009.39.
BH3-only BCL-2 family proteins are effectors of canonical mitochondrial apoptosis. They discharge their pro-apoptotic functions through BH1-3 pro-apoptotic proteins such as BAX and BAK, while their activity is suppressed by BH1-4 anti-apoptotic BCL-2 family members. The precise mechanism by which BH3-only proteins mediate apoptosis remains unresolved. The existing data are consistent with three mutually non-exclusive models (1) displacement of BH1-3 proteins from complexes with BH1-4 proteins; (2) direct interaction with and conformational activation of BH1-3 proteins; and (3) membrane insertion and membrane remodeling. The BH3-only proteins appear to play critical roles in restraining cancer and inflammatory diseases such as rheumatoid arthritis. Molecules that mimic the effect of BH3-only proteins are being used in treatments against these diseases. The cell death activity of a subclass of BH3-only members (BNIP3 and BNIP3L) is linked to cardiomyocyte loss during heart failure. In addition to their established role in apoptosis, several BH3-only members also regulate diverse cellular functions in cell-cycle regulation, DNA repair and metabolism. Several members are implicated in the induction of autophagy and autophagic cell death, possibly through unleashing of the BH3-only autophagic effector Beclin 1 from complexes with BCL-2/BCL-xL. The Chapters included in the current Oncogene Review issues provide in-depth discussions on various aspects of major BH3-only proteins.
仅含BH3结构域的BCL-2家族蛋白是典型线粒体凋亡的效应因子。它们通过BAX和BAK等含BH1-3结构域的促凋亡蛋白发挥促凋亡功能，而其活性受到含BH1-4结构域的抗凋亡BCL-2家族成员的抑制。仅含BH3结构域的蛋白介导凋亡的确切机制仍未解决。现有数据与三种相互不排斥的模型一致：（1）含BH1-3结构域的蛋白从与含BH1-4结构域的蛋白形成的复合物中被置换；（2）与含BH1-3结构域的蛋白直接相互作用并使其构象激活；（3）膜插入和膜重塑。仅含BH3结构域的蛋白似乎在抑制癌症和类风湿关节炎等炎症性疾病中起关键作用。模拟仅含BH3结构域的蛋白作用的分子正被用于治疗这些疾病。仅含BH3结构域成员的一个亚类（BNIP3和BNIP3L）的细胞死亡活性与心力衰竭期间心肌细胞丢失有关。除了在凋亡中已确定的作用外，几个仅含BH3结构域的成员还在细胞周期调控、DNA修复和代谢等多种细胞功能中发挥调节作用。几个成员与自噬和自噬性细胞死亡的诱导有关，可能是通过从与BCL-2/BCL-xL形成的复合物中释放仅含BH3结构域的自噬效应因子Beclin 1来实现。本期《癌基因综述》中的各章节对主要仅含BH3结构域蛋白的各个方面进行了深入讨论。
